Eye drop with difluprednate for macular edema treatment

ABSTRACT

The present invention aims to provide an eye drop for treating macular edema. The present invention provides an eye drop for treating macular edema, which contains difluprednate as an active ingredient. The eye drop can afford effects such as improvement of visual acuity and decreased foveal retinal thickness in macular edema.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an eye drop containing difluprednate asan active ingredient for treating macular edema.

BACKGROUND OF THE INVENTION

Macular edema is swelling of retinal macula, and the edema occurs due toa liquid diapedesis from the retinal blood vessels. The blood leaks fromweak blood vessel walls and enters into extremely small regions ofretinal macula rich in retina cone which is a nerve terminal thatdetects color and the vision during the day relies on. Next, imagesbecome blurred in the center of the central field or right beside thecenter. The visual acuity decreases progressively for months. Diabeticretinopathy, retinal blood vessel obstruction, ocular inflammation andage-related macular degeneration are all associated with the macularedema. Retinal macula is sometimes damaged by maculatumentia afterremoval of crystalline lens for the treatment of cataract.

As the conventional therapy of macular edema, photocoagulation by laserirradiation, vitreous surgery and systemic administration, intravitrealadministration and sub-Tenon administration of steroid and the like havebeen performed. The photocoagulation by laser irradiation closes theblood vessel permitting liquid diapedesis, and decreases swelling ofmacula. However, attention should be paid in laser irradiation to avoidextremely vulnerable fovea. If the fovea should be injured by thissurgery, the central visual field may be damaged. Moreover, plural lasersurgeries are often required to eliminate swelling. While vitreoussurgery is applied to a case for which a laser surgery is ineffective,it is associated with high tissue-invasive potential, sometimes causingproblems of post-surgery complications. In addition, the administrationof steroid is reported to be useful. While systemic administration ofsteroid is possible for the treatment of ocular diseases, in general, itoften causes side effects which are too severe for ophthalmologic uses.Therefore, intravitreal administration and sub-Tenon administration,which are topical administrations, have also been studied. Althoughintravitreal administration can solve some problems associated withsystemic administration, intravitreal administration of existingophthalmic compositions can cause ocular hypertension, steroid glaucomaand posterior subcapsular cataract when steroid is administered. Also,intravitreal administration of steroid sometimes causes post-surgerycomplications. sub-Tenon administration is often used in clinicalpractice to decrease the tissue-invasive potential of intravitrealadministration and burden on patients. While administration of steroiddecreases the tissue-invasive potential as compared to vitreous surgery,it is still associated with the problems of post-surgery complications.

Administration by instillation is an administration method with highmerit since it has low tissue-invasive potential. Examples of thetreatment of ophthalmic diseases by instillation of steroid include useof a 0.1% betamethasone ophthalmic solution for anti-inflammatorydiseases (blepharitis, conjunctivitis, keratitis, scleritis,episcleritis, anterior ocular segmentuveitis, postoperativeinflammation) in the external eye and the anterior ocular segment.Moreover, WO 2007/025275 describes the possibility of application ofinstillation and the like of various steroids and corticosteroidantagonists to the treatment of various ophthalmic diseases such asmacular degeneration, glaucoma, macular edema, age-related maculardegeneration, retina angiogenesis, diabetic retinopathy, iritis,posterior eye segmentuveitis and the like, while decreasing the sideeffects of steroid. However, only few cases of effectiveness ofinstillation for macular edema of the retina in clinical practice havebeen reported, and there is only one report of volume reduction ofretinal macular edema by administration of 0.1% betamethasone ophthalmicsolution for 2 weeks to one month, 6 times per day (The 43rd AnnualCongress of Japanese Retina and Vitreous Society 016-5, 2004). Thus, thetreatment of macular edema by eye drop has not been performed.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide an eye drop for the treatment ofmacular edema.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that administration of aneye drop containing difluprednate as an active ingredient improves thesymptoms of decreased visual acuity, increased foveal retinal thicknessand the like due to macular edema, which resulted in the completion ofthe present invention.

Accordingly, the present invention provides the following.

(1) An eye drop for treating macular edema, comprising difluprednate asan active ingredient.(2) The eye drop of (1), wherein the macular edema is refractory macularedema.(3) The eye drop of (1) or (2), which is an emulsion eye drop.(4) The eye drop of any of (1) to (3), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v).(5) The eye drop of any of (1) to (4), comprising 0.005-0.1% (w/v) ofdifluprednate, and castor oil, polysorbate 80, concentrated glycerin,sodium acetate, boric acid, sodium edetate and sorbic acid.(6) The eye drop of any of (1) to (5), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), a dosing period is at least 1 week,an administration frequency is 4 times per day, and a dose is 30-50 μLper administration.(7) The eye drop of any of (1) to (5), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), a dosing period is 1-4 weeks, anadministration frequency is 4 times per day, and a dose is 30-50 μL peradministration.(8) The eye drop of any of (1) to (5), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), an administration frequency is 4times per day for 4 weeks from the start of the administration and twiceper day after 4 weeks, and a dose is 30-50 μL per administration.(9) The eye drop of any of (1) to (5), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), a dosing period is not longer than 12weeks, an administration frequency is 4 times per day for 4 weeks fromthe start of the administration and twice per day after 4 weeks, and adose is 30-50 μL per administration.(10) The eye drop of any of (1) to (5), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), a dosing period is at least 12 weeks,an administration frequency is 4 times per day for 4 weeks from thestart of the administration and twice per day after 4 weeks, and a doseis 30-50 μL per administration.(11) A method of treating macular edema in a mammal, comprisinginstilling an eye drop containing an effective amount of difluprednateto the mammal.(12) The method of (11), wherein the macular edema is refractory macularedema.(13) The method of (11) or (12), wherein the eye drop is an emulsion eyedrop.(14) The method of any of (11) to (13), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v).(15) The method of any of (11) to (14), wherein the eye drop comprises0.005-0.1% (w/v) of difluprednate, and castor oil, polysorbate 80,concentrated glycerin, sodium acetate, boric acid, sodium edetate andsorbic acid.(16) The method of any of (11) to (15), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), and the eye drop isadministered for at least 1 week, 4 times per day, in a dose of 30-50 μLper administration.(17) The method of any of (11) to (15), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), and the eye drop isadministered for 1-4 weeks, 4 times per day, in a dose of 30-50 μL peradministration.(18) The method of any of (11) to (15), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), and the eye drop isadministered 4 times per day for 4 weeks from the start of theadministration and twice per day after 4 weeks, in a dose of 30-50 μLper administration.(19) The method of any of (11) to (15), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), and the eye drop isadministered for not longer than 12 weeks, 4 times per day for 4 weeksfrom the start of the administration and twice per day after 4 weeks, ina dose of 30-50 μL per administration.(20) The method of any of (11) to (15), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), and the eye drop isadministered for at least 12 weeks, 4 times per day for 4 weeks from thestart of the administration and twice per day after 4 weeks, in a doseof 30-50 μL per administration.(21) An eye drop containing difluprednate for use in the treatment ofmacular edema.(22) The eye drop of (21), wherein the macular edema is refractorymacular edema.(23) The eye drop of (21) or (22), which is an emulsion eye drop.(24) The eye drop of any of (21) to (23), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v).(25) The eye drop of any of (21) to (24), comprising 0.005-0.1% (w/v) ofdifluprednate, and castor oil, polysorbate 80, concentrated glycerin,sodium acetate, boric acid, sodium edetate and sorbic acid.(26) The eye drop of any of (21) to (25), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), and the eye drop is administered forat least 1 week, 4 times per day, in a dose of 30-50 μL peradministration.(27) The eye drop of any of (21) to (25), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), and the eye drop is administered for1-4 weeks, 4 times per day, in a dose of 30-50 μL per administration.(28) The eye drop of any of (21) to (25), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), and the eye drop is administered 4times per day for 4 weeks from the start of the administration and twiceper day after 4 weeks, in a dose of 30-50 μL per administration.(29) The eye drop of any of (21) to (25), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), and the eye drop is administered fornot longer than 12 weeks, 4 times per day for 4 weeks from the start ofthe administration and twice per day after 4 weeks, in a dose of 30-50μL per administration.(30) The eye drop of any of (21) to (25), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), and the eye drop is administered forat least 12 weeks, 4 times per day for 4 weeks from the start of theadministration and twice per day after 4 weeks, in a dose of 30-50 μLper administration.(31) Use of difluprednate for the production of an eye drop for treatingmacular edema.(32) The use of (31), wherein the macular edema is refractory macularedema.(33) The use of (31) or (32), wherein the eye drop is an emulsion eyedrop.(34) The use of any of (31) to (33), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v).(35) The use of any of (31) to (34), wherein the eye drop comprises0.005-0.1% (w/v) of difluprednate, and castor oil, polysorbate 80,concentrated glycerin, sodium acetate, boric acid, sodium edetate andsorbic acid.(36) The use of any of (31) to (35), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), the dosing period ofthe eye drop is at least 1 week, the administration frequency is 4 timesper day, and the dose is 30-50 μL per administration.(37) The use of any of (31) to (35), wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v), the dosing period ofthe eye drop is 1-4 weeks, the administration frequency is 4 times perday, and the dose is 30-50 μL per administration.(38) The use of any of (31) to (35), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), the administration frequency is 4times per day for 4 weeks from the start of the administration and twiceper day after 4 weeks, and the dose is 30-50 μL per administration.(39) The use of any of (31) to (35), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), the dosing period of the eye drop isnot longer than 12 weeks, the administration frequency is 4 times perday for 4 weeks from the start of the administration and twice per dayafter 4 weeks, and the dose is 30-50 μL per administration.(40) The use of any of (31) to (35), wherein the concentration ofdifluprednate is 0.005-0.1% (w/v), the dosing period of the eye drop isat least 12 weeks, the administration frequency is 4 times per day for 4weeks from the start of the administration and twice per day after 4weeks, and the dose is 30-50 μL per administration.

Effect of the Invention

According to the present invention, macular edema can be treated with aneye drop. Particularly, the eye drop of the present invention is usefulfor treating refractory macular edema.

EMBODIMENT OF THE INVENTION

The present invention relates to an eye drop for treating macular edema,which contains difluprednate as an active ingredient.

Difluprednate (6α,9α-difluoroprednisolone 17-butyrate 21-acetate) is asteroidal anti-inflammatory drug like betamethasone phosphate andtriamcinolone, and is known to show a superior anti-inflammatory actionby transdermal administration and the like. In addition, an eye dropthereof is used for the prophylaxis or treatment of inflammation aftersurgery and for the prophylaxis or treatment of ocular pain aftersurgery.

Macular edema is swelling of retinal macula, and the edema occurs due toa liquid leakage from the retinal blood vessels. Macular edema isobserved as increased foveal retinal thickness of macula. While thefoveal retinal thickness of healthy human varies depending on theindividual differences and age, the average value thereof is reported tobe 178 μm (Br J Ophthalmol. 1998 September; 82(9): 1003-6). For thetreatment of macular edema, photocoagulation by laser irradiation,vitreous surgery, systemic administration of steroid, intravitrealadministration and sub-Tenon administration have conventionally beenemployed as mentioned above, and a certain level of therapeutic effectis found by these treatment methods in some macular edema. On the otherhand, it is known that these conventional treatment methods cannotprovide a sufficient effect for some macular edema. In the presentinvention, refractory macular edema refers to macular edema for which asufficient effect cannot be afforded by the conventionally-employedtreatments (e.g., any one or more of photocoagulation by irradiation,vitreous surgery, systemic administration of steroid, intravitrealadministration and sub-Tenon administration).

In the present invention, a sufficient treatment effect means that thefoveal retinal thickness decreases by not less than 20%. In addition,improvement of log MAR value by not less than 0.2 unit is alsoconsidered a sufficient effect. This is a general diagnostic criteriumin ophthalmic treatments (FDA/NEI protocol (NEI/FDA Ophthalmic ClinicalTrial Design and Endpoints Meeting, 2006)).

The log MAR (the log of the minimum angle of resolution) value shows theability of the eye (visual acuity) to distinguish the minimum separableacuity, which can be determined by logarithmically converting the valuesmeasured using a decimal visual acuity chart.

The foveal retinal thickness is a value from the internal limitingmembrane to the visual cell inner segment-outer segment junction in thefovea, and can be measured by Cirrus OCT (registered trade mark, CarlZeiss), 3D OCT-1000 (registered trade mark, TOPCON CORPORATION) and thelike.

The eye drop containing difluprednate as an active ingredient relatingto the present invention may take any form of emulsion or suspension. Inview of the tissue transitivity of difluprednate, particularly preferredis an emulsion eye drop in the form of an emulsion. Examples of suchemulsion eye drop include Durezol (registered trade mark, SirionTherapeutics, USA). Durezol is a preparation obtained by emulsifying amixture of difluprednate and predetermined sub-components for thepurpose of enabling difluprednate, the active ingredient, toappropriately penetrate into the eyeball and act on the affected part.

When the eye drop of the present invention is an emulsion, it can beprepared according to, for example, U.S. Pat. No. 6,114,319(JP-B-3410364).

When the eye drop of the present invention is a suspension, it can beprepared according to, for example, U.S. Pat. No. 5,556,848(JP-B-3781792).

The concentration of difluprednate contained in the eye drop of thepresent invention is preferably 0.005-0.1% (w/v), more preferably0.025-0.1% (w/v), particularly preferably 0.05% (w/v).

The eye drop of the present invention can be used after mixing withvarious known pharmaceutically acceptable substances appropriatelyselected with the aim of adjusting the tissue transitivity uponinstillation and the like.

Examples of the pharmaceutically acceptable components include oils(e.g., castor oil, peanuts oil, cottonseed oil, soybean oil, olive oil,medium-chain triglyceride etc.), solvents (e.g., saline, sterilizationpurified water etc.), stabilizers (e.g., sodium edetate, citric acidetc.), emulsifiers (e.g., polyvinylpyrrolidone etc.), suspending agents(e.g., hydroxypropylmethylcellulose, methylcellulose,hydroxymethylcellulose etc.), surfactants (e.g., polysorbate 80,polyoxyethylene hydrogenated castor oil etc.), preservatives (e.g.,benzalkonium chloride, parabens, chlorobutanol etc.), buffers (e.g.,boric acid, borax (sodium borate), sodium acetate, citrate buffer,phosphate buffer etc.), isotonicity agents (e.g., sodium chloride,glycerol, mannitol etc.), pH adjusters (e.g., hydrochloric acid, sodiumhydroxide etc.) and the like. These various known substances can beappropriately selected and used according to the object.

Particularly, when the eye drop of the present invention is used as anemulsion, it desirably contains a surfactant as an emulsifier. As thesurfactant, a nonionic surfactant and the like can be added. Examples ofthe nonionic surfactant include polyoxyethylene hydrogenated castor oilsor polyoxyethylene sorbitan fatty acid ester, preferably sorbitanpolyoxyethylene monooleates, polyoxyethylene sorbitan monolaurates,sorbitan polyoxyethylene monopalmitates, sorbitan polyoxyethylenemonostearates and the like. Among these, castor oil and polysorbate 80are preferably contained. Examples of other components that can becontained include concentrated glycerin, sodium acetate, boric acid,sodium edetate and sorbic acid. Particularly preferred are concentratedglycerin, sodium acetate, boric acid, sodium edetate and sorbic acid,which are preferably contained as necessary.

The eye drop of the present invention can be safely administered tomammals (human, dog, rabbit, bovine, horse, monkey, cat, sheep etc.).

While the dose of the eye drop of the present invention varies dependingon the level of condition, age and body weight of patient, and the like,for example, an eye drop containing 0.005-0.1% (w/v) of difluprednate ispreferably administered to an adult about 2-4 times per day byinstillation of 1-2 drops (preferably 1 drop: about 30-50 μL) peradministration.

In addition, while the dosing period of the eye drop of the presentinvention varies depending on the level of condition and the like, forexample, it is at least about 1 week, preferably about 1-4 weeks, morepreferably about not less than 4 weeks, more preferably not longer thanabout 12 weeks. Depending on the level of condition and the like,however, administration exceeding 12 weeks may be performed.

In a preferable administration mode, for example, the dosing period ofthe eye drop of the present invention with a difluprednate concentrationof 0.005-0.1% (w/v) is at least 1 week, the administration frequency is4 times per day, and the dose is about 30-50 μL per administration.

In another preferable administration mode, for example, the dosingperiod of the eye drop of the present invention with a difluprednateconcentration of 0.005-0.1% (w/v) is 1-4 weeks, the administrationfrequency is 4 times per day, and the dose is about 30-50 μL peradministration.

In a still another preferable administration mode, the administrationfrequency of the eye drop of the present invention with a difluprednateconcentration of 0.005-0.1% (w/v) is 4 times per day for 4 weeks fromthe start of the administration, twice per day after 4 weeks, and thedose is about 30-50 μL per administration.

In a yet another preferable administration mode, the dosing period ofthe eye drop of the present invention with a difluprednate concentrationof 0.005-0.1% (w/v) is not longer than 12 weeks, the administrationfrequency is 4 times per day for 4 weeks from the start of theadministration, twice per day after 4 weeks, and the dose is about 30-50μL per administration.

In other preferable administration mode, the dosing period of the eyedrop of the present invention with a difluprednate concentration of0.005-0.1% (w/v) is at least 12 weeks, the administration frequency is 4times per day for 4 weeks from the start of the administration, twiceper day after 4 weeks, and the dose is about 30-50 μL peradministration.

EXAMPLES Example 1

The following results were obtained by the clinical tests(UMIN000001432) approved by the Ethics Committee of the YamagataUniversity Faculty of Medicine.

For confirmation of the efficacy of the eye drop of the presentinvention, the eyes of 11 patients with macular edema (16 eyes) weretreated by instillation of 0.05% (w/v) difluprednate emulsion eye drop(Durezol). The patient group instilled with Durezol included patientswho received treatment by sub-Tenon administration of triamcinolone(n=8), intravitreal administration of triamcinolone (n=4), vitreoussurgery (n=10) or intravitreal administration of bevacizumab (n=2) (withtherapeutic duplication). In addition, photocoagulation was applied to12 eyes, and an intraocular lens was implanted in 11 eyes. Thus, thepatients subjected to the treatment were those who had underwentconventionally-known treatments of macular edema, and were in variousconditions particularly due to vitreous surgery and intraocular lensimplant. They were patients diagnosed with refractory macular edema whoresist improvement of retinal edema near fovea even by these treatmentsand still have a greater foveal retinal thickness than healthy human.The clinical test was performed by instillation of Durezol to allpatients after lapse of not less than 3 months from the previoustreatment. The instillation of Durezol was performed 4 times per day forthe first 1 month, twice per day for 2 months thereafter. In addition,the dose per administration was 1 drop (about 30-50 μl). The formulationof Durezol is as follows.

difluprednate 0.05 g castor oil 5.0 g polysorbate 80 4.0 g concentratedglycerin 2.2 g sodium acetate 0.05 g boric acid 0.1 g sodium edetate0.02 g sorbic acid 0.1 g sterile purified water total amount 100 mL

As a control group, 17 eyes of 9 patients from among patients with theonset of diabetic macular edema were adopted, who were comparable to theDurezol administration group in the age, sex, duration of diabetes andthe level of retinopathy. The control group consists of patients beforeundergoing treatments of macular edema, such as sub-Tenon administrationof steroid, intravitreal administration of steroid, vitreous surgery andthe like. This control group was administered with a 0.1% (w/v)ophthalmic solution of betamethasone sodium phosphate (Rinderon A,registered trade mark) 6 times per day for 1 month. The betamethasonephosphate eye drop is a steroid preparation generally used as ananti-inflammatory agent for anterior ocular segment in the same manneras an eye drop containing difluprednate.

The above-mentioned administration conditions of Rinderon A are thosefor the administration of Rinderon A in a test (steroid responder test)previously confirming the level of intraocular pressure increase causedby sub-Tenon administration or intravitreal administration of steroidsuch as triamcinolone and the like for the treatment of macular edema.The steroid responder test aims to test the sensitivity of individualpatient to steroid by measuring the level of intraocular pressureincrease resulting from the action, inside the eyeball, of betamethasonephosphate administered by instillation, and it clarifies whether or notmacular edema can be treated by intravitreal administration and the likeof steroid.

The patients in the Examples of the present invention and the patientsin the control group were subjected to the visual acuity test andmeasurement of decrease rate of the foveal retina thickness using CirrusOCT (Carl Zeiss), according to the FDA/NEI protocol (NEI/FDA OphthalmicClinical Trial Design and Endpoints Meeting, 2006). For the judgment ofeffectiveness of the instillation treatment, improvement of not lessthan 0.2 unit in the log MAR value by instillation was judged to beeffective for improvement of visual acuity, or not less than 20% ofdecrease rate of the foveal retinal thickness was judged to beeffective. In addition, the effectiveness rate was calculated as aproportion (%) of the number of cases effective for the improvement ofvisual acuity and foveal retinal thickness decrease rate to the totalnumber of cases.

Table 1 shows the effects of the Durezol instillation and Rinderon Ainstillation on the foveal retinal thickness decrease rate in macularedema. The effectiveness rate of the foveal retinal thickness decreaseis 37.5% in the Durezol administration group at the time point of 1month from the start of the administration, which clearly shows that thesymptom of macular edema is improved. In contrast, in the Rinderon Aadministration group (control group) (Rinderon A is used as ananti-inflammatory agent for the anterior ocular segment like Durezol), adecrease in the foveal retinal thickness was found in a small portion ofpatients; however, the effectiveness rate to the total number ofpatients was extremely low as compared to the Durezol administrationgroup. Considering that the patients of the Durezol administration groupare difficult to treat for edema as compared to the patients of theRinderon A administration group, it is clear that the eye drop ofdifluprednate of the present invention shows efficacy not obtainable bya betamethasone phosphate eye drop, which is a similar steroidpreparation. In addition, it is clear that the difluprednate eye drop isalso effective for refractory macular edema, which is difficult to treatby conventional treatment methods.

Table 2 shows time-course changes in the effect of Durezol instillationon the foveal retinal thickness decrease rate. Continuous instillationof Durezol to macular edema patients provides continuous increase in theeffectiveness rate, continuous decrease in the average retina thicknessof the patients, and administration for 3 months can afford an extremelyhigh effectiveness rate of 61.5%. While the patients of the Durezoladministration group had experience of various conventionally-knowntreatments before the Durezol instillation treatment, similareffectiveness was achieved by the Durezol administration regardless ofthe treatment history such as vitreous surgery and the like. Thisindicates that the instilled difluprednate preparation directly acts onthe edema site of the macula part. The effect of the eye drop of thepresent invention is not limited for refractory macular edema, and asimilar edema-improving effect is also expected in general patients withmacular edema, whose conditions can be improved more easily.

Table 3 shows the effect of Durezol for improvement of visual acuity inmacular edema. Table 4 shows time course changes of the effectivenessrate by the Durezol administration in the improvement of visual acuity.Improvement of visual acuity by the treatment of macular edema requiresa comparatively long time after improvement of edema in the macula part,and therefore, it is generally difficult to confirm improvement ofvisual acuity during a short-term treatment. However, apparentimprovement of visual acuity was found in a short time in a part of theDurezol administration group, thus showing the effectiveness of thedifluprednate eye drop as a method for treating macular edema. On theother hand, an effectiveness rate relative to the improvement of visualacuity was not confirmed in the control Rinderon A administration group.Rinderon A is a steroid used by instillation as an anti-inflammatoryagent for the anterior ocular segment, as well as for a steroidresponder test in patients with macular edema, as mentioned above, andthe results are consistent with the absence of improvement of visualacuity in the steroid responder test.

TABLE 1 effectiveness rate after 1 month from start of administrationRinderon A  5.9% Durezol 37.5%

TABLE 2 average value after effectiveness (μm) of foveal administrationrate retinal thickness 1 week 37.5% 407.69 1 month 37.5% 376.13 2 months53.3% 327.38 3 months 61.5% 302.23

TABLE 3 effectiveness rate after 1 month from start of administrationRinderon A 0.0% Durezol  31%

TABLE 4 after effectiveness administration rate 1 week 13% 1 month 31% 2months 13% 3 months 31%

INDUSTRIAL APPLICABILITY

An eye drop containing difluprednate of the present invention as anactive ingredient has enabled improvement of edema in macular edemapatients by instillation, which is an administration method with lowtissue invasiveness as compared to conventional methods employed inclinical practice. The effects on foveal retinal thickness and visualacuity are superior to those of a betamethasone phosphate eye drop, forwhich experimental example of instillation administration has beenreported. Moreover, effective results can also be obtained in patientswith recurrent refractory macular edema, who received sub-Tenonadministration or intravitreal administration of triamcinolone, vitreoussurgery or intravitreal administration of bevacizumab in the past.

The present invention is based on JP 2009-165924 (filing date: Jul. 14,2009) filed in Japan, the contents of which are hereby incorporated byreference.

1-10. (canceled)
 11. A method of treating macular edema in a mammal,comprising instilling an eye drop containing an effective amount ofdifluprednate to the mammal.
 12. The method according to claim 11,wherein the macular edema is refractory macular edema.
 13. The methodaccording to claim 11, wherein the eye drop is an emulsion eye drop. 14.The method according to claim 11, wherein the concentration ofdifluprednate in the eye drop is 0.005-0.1% (w/v).
 15. The methodaccording to claim 11, wherein the eye drop comprises 0.005-0.1% (w/v)of difluprednate, and castor oil, polysorbate 80, concentrated glycerin,sodium acetate, boric acid, sodium edetate and sorbic acid.
 16. Themethod according to claim 11, wherein the concentration of difluprednatein the eye drop is 0.005-0.1% (w/v), and the eye drop is administeredfor at least 1 week, 4 times per day, in a dose of 30-50 μL peradministration.
 17. The method according to claim 11, wherein theconcentration of difluprednate in the eye drop is 0.005-0.1% (w/v), andthe eye drop is administered for 1-4 weeks, 4 times per day, in a doseof 30-50 μL per administration.
 18. The method according to claim 11,wherein the concentration of difluprednate in the eye drop is 0.005-0.1%(w/v), and the eye drop is administered 4 times per day for 4 weeks fromthe start of the administration and twice per day after 4 weeks, in adose of 30-50 μL per administration.
 19. The method according to claim11, wherein the concentration of difluprednate in the eye drop is0.005-0.1% (w/v), and the eye drop is administered for not longer than12 weeks, 4 times per day for 4 weeks from the start of theadministration and twice per day after 4 weeks, in a dose of 30-50 μLper administration.
 20. The method according to claim 11, wherein theconcentration of difluprednate in the eye drop is 0.005-0.1% (w/v), andthe eye drop is administered for at least 12 weeks, 4 times per day for4 weeks from the start of the administration and twice per day after 4weeks, in a dose of 30-50 μL per administration. 21-40. (canceled)